SIROP CONTENANT DE LA N-ACETYLCYSTEINE

SYRUP CONTAINING N-ACETYL-CYSTEINE

Abrégé anglais

A syrup containing N-acetyl-cysteine, stable for at least two years having
pleasant taste and smell, consists of an aqueous solution of
NAC, a sweetening agent and a thickening agent. The solution can also contain
a flavouring agent and a preservative. The pH is between
and 8.

Revendications

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CLAIMS
1. A composition in the form of a syrup containing (each 100 ml):
- N-acetyl-cysteine ~~~~2 - 4.2 g/100ml
- a sweetening agent ~~~0.02 - 0.3 g/100ml
- a thickening agent selected among:
sodium carboxymethylcellulose and
hydroxypropylmethylcellulose or
mixtures thereof ~~~~0.1 - 4 g/100ml
and further
- water q.s. to 100 ml
pH being settled within the interval 5-8.
2. A composition according to claim 1, wherein said composition further
contains
a flavouring agent in an amount of (0.1 - 0.4 g/100ml).
3. A composition according to claim 1, wherein said composition further
contains
a preservative in an amount of (0.05 - 0.5 g/100ml).
4. A composition according to claim 1, wherein said composition further
contains
a flavouring agent in the amount of (0.1 - 0.4 g/100ml) and a preservative in
the amount of
(0.05 - 0.5 g/100ml).
5. A composition according to claim 3 or claim 4, wherein said preservative is
selected from the group consisting of sodium edetate, sodium benzoate, methyl
4-
hydroxybenzoate, propyl 4-hydroxybenzoate and mixtures thereof.

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6. A composition according to any one of claims 1 to 5, wherein said
sweetening
agent is selected from the group consisting of saccharin, sodium saccharin,
and cyclamates or
mixtures thereof.
7. A composition according to any one of claims 1 to 6, wherein the pH is
between
6.5 and 7.

Description

WO 94/12168 PCT/EP93/03280
SYRUP CONTAINING N-ACETYL-CYSTEINE
The present invention relates to a composition in the form of a
syrup containing N-acetyl-cysteine as active ingredient.
N-acetyl-cysteine (hereinafter briefly referred to as NAC) is a
pharmacological properties,
compound endowed with several useful
making it a widely used drug.
In the treatment of cold diseases, NAC showed to be useful thanks to
its mucolytic properties.
One of the pharmaceutical forms largely used in the therapy of cold
diseases is syrup, particularly suitable also for pediatric use.
NAC is available in several pharmaceutical forms, however the high
reactivity of the molecule, the relative instability and the
characteristic sulphureous smell and taste make extremely
troublesome the achievement of liquid forms for oral use which are
time-stable and with a good palatability.
The preparation of a syrup provides, practically in ail the cases,
the use of a disaccharide (sucrose) or of a simple sugar as a
sweetening and thickening agent of the aqueous solution of the drug.
However, the interaction of NAC with sugars gives to the solution an
unacceptable brown colouring and the titre of NAC decreases.
Thus, it is not possible to leave NAC in solution for a long time in
the presence of sucrose.
Similarly, the reactions giving brown colour and causing bad smell
take place also between NAC and the monosaccharides whose use is
described in the French patent application No. 2631831 in the name
of Calco Anstalt.
' As far,as we know, the only syrup formulation containing NAC on the
market consists in a composition to be prepared at the moment of use
by dissolution in water of a granulate.
After preparation, the extemporaneous syrup must be used within 3

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x
weeks. '
We have now surprisingly found that it is possible to prepare a
time-stable NAC syrup having a pleasant taste without using sugars.
Therefore, object of the present invention is a composition in the
form of a syrup containing (each 100 ml>:
- N-acetyl-cysteine 2 -4.2 g/100 mi
- a sweetening agent 0.02-0.3 g/100 ml
- a thickening agent selected among:
sodium carboxymethylcellulose and
hydroxypropylmethylcellulose or
mixtures thereof 0.1 -4 g/100 mI
and optionally:
- a flavouring agent 0.1 -0.4 g/100 mi
~5 - a preservative 0.05-0.5 g/100 ml
and further
- water q.s. to 10o ml
pH being settled within the interval 5-8. .
The above solution results to be stable in a closed bottle under
inert gas for at least 2 years under environmental conditions. When
the bottle is opened, the solution shows to have a pleasant taste
and to be free from bad smells; NAC maintains the initial titre and
the open syrup results to be stable for at least 5 weeks.
For sweetening agent we mean a substance able to give a sweet taste
to the solution but wick does not contain sugars. Specific examples
of sweetening agents are saccharin, sodium saccharin and cyclamates
or mixtures thereof.
The amount of sweetening agent will be the minimum amount sufficient
to give a pleasant taste to the solution.
The thickening agent is selected among sodium carboxymethyicelluiose

O 94/12168 ~ ~ ~ PCTIEP93/03280
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methylcellulose and hydroxypropylmethyleellulose or mixtures
thereof. Surprisingly, these substances showed to be compatible with
NAC and to be able to give to the solution a thickness suitable for
the usual palatability of a syrup.
To these three base components cNAC, sweetening agent and thickening
agent) water can~be added up to the selected volume, by optionally
rectifying the resultant pH so that it is maintained within the
interval from 5 to 8. Preferably, pH will be from b.5 to 7.
The syrup could also, but not necessarily, contain a flavouring
agent in order to improve the palatability, especially for pediatric
use.
Since the syrup is generally manufactured in absence of asepsis,
pharmacopoeiae require the compulsory presence of a preservative.
The preservative is further required to assure the microbioiogicai
quality during the time of use by the patient.
In this case, preservatives selected among sodium benzoate, methyl
4-hydroxybenzoate, propyl 4-hydroxybenzoate and mixtures thereof
will be preferably used.
With the double function of preservative and of metal cheiating
agent also sodium EDTA could be used in addition to or in partial
substitution of the above preservatives.
The preparation of the syrup according to the present invention is
carried out under inert gas by simple dissolution of the substances
in the predetermined amount of water.
The resultant solution is shared into multidose bottles or in
single-dose containers.
The packaging of multi-dose bottles could provide the contemporaneous
supplying of a graduated measure for the correct dosage of the
single doses for grown-up people (for example 10 ml> or for children

WO 94/12168 PCT/EP93/03280
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(for example 5 ml).
In order to better illustrate the present invention the following
examples are now given.
Example 1
f
liters of a syrup containing teach 100 ml>:
NAC 2.1 g
Saccharin 0.04 g
Sodium carboxymethylcellulose 0.2 g
10 Sodium benzoate 0.15 g
Sodium edetate 0.1 g
Raspberry flavour 0.25 g
Water q.s. to 100 ml
were prepared by simple dissolution of the substancespurified
in
and de-aerated water under nitrogen atmosphere.
The pH of the resultant solution was rectified
to the correct vdiue
6.5 by addition of sodium hydroxide.
The solution was shared at the rate of 150 ml/bottle.
The bottles were stored for 2 years at room temperature.
After this period, the titre of NAC resulted to than 95i
be higher
of the initial one.
Such a titre resulted to be higher than 90r, of one also
the initial
after 5 weeks from the opening of the bottle.
The syrup, also after 2 years of storage, showed pleasant
to have a
taste and smell and a good general palatability.
Example 2
10 1 of a syrup having the following composition mi>:
(each 100
NAC 2.1 g
Sodium saccharin 0.04 g
Hydroxypropylmethylcellulose 0.2 g

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Methyl 4-hydroxybenzoate 0.1 g
Sodium edetate 0.1 g
Apricot flavour 0.1 g
Water q.s. to 100 ml
were prepared by dispersion of hydroxypropylmethylceilulose in a
part of boiling water which was cooled to room temperature. After
hydration of hydroxypropylmethylcellulose, it was poured into a
solution obtained by dissolving all the remaining substances in
purified and de-aerated water, under nitrogen atmosphere.
The pH of the solution was rectified to pH b,5 with sodium
hydroxide.
The solution was shared into single-dose sachets of 10 mi each
containing about 200 mg of NAC.
~5 Example 3
10 1 of a syrup having the following composition (each 100 mi>:
NAC 2.1 g
Sodium saccharin 0.04 g
Hydroxypropylmethylcellulose 0.2 g
Sodium edetate o.1 g
Apricot flavour 0.1 g
Water q.s. to 100 ml
were prepared by dispersion of hydroxypropylmethylcellulose in a
part of boiling water which was cooled to room temperature. After
hydration of hydroxypropylmethylcellulose, it was poured into a
solution obtained by dissolving all the remaining substances in
' purified and de-aerated water, under nitrogen atmosphere.
The pH of the solution was rectified to pH b.5 with sodium
hydroxide.
The solution was shared into single-dose glass vials of 10 mi with

WO 94/12168 PCT/EP93/03280
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rubber stopper each containing about 200 mg of NAC.
Example 4
By working as described in Example 1, 10 1 of syrup having the
following composition (each 100 ml> were prepared: ,
4.2 g
NAC
Sodium saccharin 0~08 g
Sodium carboxymethylcelluiose 0.20 g
Sodium benzoate 0.15 g
Sodium edetate 0.10 g
Raspberry flavour 0.4 g
Water q.s. to 100 ml
The pH of the solution was rectified to pH 6.5 with sodium
hydroxide.
The solution was shared into bottles at the rate of 150 ml each
bottle.
Example 5
By working as described in Example 2, 10 1 of syrup having the
following composition (each 100 ml) were prepared:
20 NAC 2.1o g
Saccharin 0.04 g
Hydroxypropylmethylcellulose 0.40 g
Methyl 4-hydroxybenzoate 0.10 g
Banana flavour 0.4 g
25 Water q.s. to 100 ml
G
The pH of the solution was rectified to pH 7 with sodium hydroxide.
The solution was shared into bottles at the rate of 450 mI each '
bottle.